Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer

Araujo, Jhajaira M.; Gomez, Andrea C.; Aguilar, Alfredo; Salgado, Roberto; Balko, Justin M.; Bravo, Leny; Doimi, Franco D.; Bretel, Denisse; Morante, Zaida; Flores, Claudio; Gómez, Henry; Pinto, Joseph A.

doi:10.1038/s41598-018-23099-7

Cited by 78 publications

(63 citation statements)

References 48 publications

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“…Substantial evidence has indicated that certain chemokines and complement components contribute to the recruitment and activation of lymphocytes . Our data indicate that the increased level of CCL5 is induced by PGLYRP2 (Fig.…”

Section: Discussionsupporting

confidence: 61%

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2020

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Background and Aims Hepatocellular carcinoma (HCC) is linked to immunosuppression. Relieving immunosuppression has been an attractive strategy to improve the efficacy of cancer immunotherapy. Peptidoglycan recognition protein 2 (PGLYRP2) is a pattern recognition receptor which is specifically expressed in liver and implicated in the regulation of innate immunity and immunosurveillance. However, the role of hepatic PGLYRP2 in modulating immune responses against HCC remains to be investigated. Approach and Results In this study, we investigated whether PGLYRP2 is able to influence HCC progression through regulating host antitumor immune responses. We demonstrated that PGLYRP2 was down‐regulated in HCC, which was linked with poor prognosis in patients (P < 0.001). PGLYRP2 overexpression in HCC cells significantly enhanced antitumor immune responses in immune‐competent mice and elevated immune response rates of peripheral blood mononuclear cells against HCC. Mechanistically, DNA methyltransferase 3A–mediated promoter hypermethylation was responsible for the down‐regulation of PGLYRP2 in HCC. PGLYRP2 promoted production of chemokine (C‐C motif) ligand 5 (CCL5) in HCC through binding to the CCL5 promoter, which contributed to the enhanced antitumor immunity. Conclusions We provide evidence that tumor‐derived PGLYRP2 acts as a candidate biomarker for adequate immune response against HCC and improved patient outcomes, indicating the importance of hepatic PGLYRP2 in cancer immunosurveillance and in designing immunotherapeutic approaches.

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Section: Discussionsupporting

confidence: 61%

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2020

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“…High density of TAMs has been linked with cancer progression, including breast PTs (12,15), suggesting that macrophages are recruited into tumor tissues and then undergo repolarization into TAM phenotype. The CCL5-CCR5 axis has been reported to recruit macrophages in several pathologic processes, such as obesity and breast cancers (20,21). We confirmed the ability of CCL5 to recruit monocytes by using monocytes from heathy donors ( Supplementary Fig.…”

Section: Malignant Pt Recruits and Induces Macrophages To A Tam-like supporting

confidence: 70%

Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy

Nie

Huang

Guo

et al. 2019

Clinical Cancer Research

105

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Purpose: Malignant phyllodes tumor (PT) is a fastprogression neoplasm derived from periductal stromal cells of the breast, which currently still lack effective treatment strategies. Our previous studies showed that the high density of tumor-associated macrophages (TAM) plays an important role in the malignant progression of PTs. TAMs secreted large amount of CCL18 to promote myofibroblast differentiation and invasion via binding to its receptor PIPTNM3 on myofibroblasts. Herein, we investigate the mechanism of how TAMs are recruited and repolarized by PTs to drive the malignant progression.Experimental Design: The cytokines secreted by PTs were identified by the cytokine array. The clinical and pathologic correlations of the cytokine with PTs were estimated with IHC. The mechanisms of the cytokine that recruited and polarized the macrophage were explored with a coculture model of primary PT cells and macrophages in vitro and in vivo. The patient-derived xenografts (PDX) of malignant PTs were used to evaluate the therapeutic effect of CCR5 inhibitor.Results: A high level of malignant PT-secreted CCL5 correlated with poor outcome of PTs and could be an independent prognostic factor of PTs. CCL5 bound to its receptor, CCR5, on macrophages thus activated AKT signaling to recruit and repolarize TAMs. Subsequently, the TAMs released CCL18 to further promote the aggressive phenotype of malignant PTs by enhancing and maintaining the myofibroblast differentiation and invasion in vitro and in vivo. In a murine PDX model of human malignant PTs, the CCL5-CCR5 axis blocked by maraviroc, an FDA-proved CCR5 inhibitor, prevented recruitment of monocytes to the tumor and dramatically suppressed tumor growth.Conclusions: Our findings indicate that malignant PTs recruit and repolarize TAMs through a CCL5-CCR5-driven signaling cascade. Thus, a positive feedback loop of CCL5-CCR5 and CCL18-PIPTNM3 between myofibroblast and TAMs is constituted to drive the malignant progression of PTs. Furthermore, targeting CCR5 with maraviroc represents a potential clinically available strategy to treat malignant PTs.

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“…Our in silico analyses, assessing the prognosis value of CCL5 expression, showed that low CCL5 expression predicted a poor survival in BC and TNBC. These findings are in agreement with certain previous reports (43,44) but contradict others (13). These discrepancies could be due to several reasons including the size of the study population.…”

Section: Discussionsupporting

confidence: 91%

“…However, we and others showed that tumor-derived CCL5 expression did not significantly promote mammary carcinoma growth (10,49), but the hematopoietic CCL5 played the major role in BC progression by regulating myeloid cells or macrophages in different subtype of BC (10,50). Two recent studies suggested that intertumoral CCL5 level determined the recruitment of CD8 + T-cell in TNBC (43,51). CCL5 might influence tumor growth by regulating different tumor-infiltrating immune cells in different subtypes of BC.…”

Section: Discussionmentioning

confidence: 85%

“…It could be expected that high CCL5 levels at the tumor site would result in the recruitment of CD8 + T cells and sustain their cytotoxic capability against tumor cells. CCL5 expression is indeed associated with accumulation of CD8 + infiltrating T cells and associated with a favorable prognosis in colon cancer (42) and breast cancer (43). The risk allele of two SNPs in CCL5 gene corresponds with a lower CCL5 expression, which leads to a depletion of CD8 + infiltrating T cells, and, impairment of CD8 + T cell function and thus a higher risk of malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

et al. 2019

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Triple-negative breast cancer (TNBC) accounts for ∼15-20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

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Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer

Cited by 78 publications

References 48 publications

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

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